Biomarker study suggests it can halt progression in most difficult cases

Action Points

Note that this observational study of patients with rheumatoid arthritis found that low-dose methotrexate was sufficient as monotherapy to induce remission in some patients.

Be aware that only patients on methotrexate for at least 7 months were included, potentially biasing the findings towards a methotrexate benefit.

Half of patients with rheumatoid arthritis (RA) considered to have a poor prognosis by European League Against Rheumatism (EULAR)/American College of Rheumatology (ACR) criteria exhibited structural remission over 3 years with only low-dose methotrexate, according to Japanese researchers.

Those patients were identifiable through having relatively low levels of serum matrix metalloproteinase-3 (MMP-3) at the outset of methotrexate monotherapy, Kazuko Shiowaza, of Kohnan Kakogawa Hospital, Japan, and colleagues reported in Arthritis Research & Therapy.

Surprisingly, "we found that a substantial proportion of patients with RA fared well with just methotrexate monotherapy: they did not exhibit radiographic evidence of progression and did not require combination therapy," the investigators wrote.

They added, "This result was in part due to the careful monitoring of patients and to the availability of other treatment options to individuals who exhibited active disease and/or adverse events."

Because of national healthcare regulations unique to Japan at the time of their study, low-dose methotrexate was commonly prescribed as initial treatment for RA. Shiowaza and colleagues assessed the efficacy of methotrexate monotherapy in 161 RA patients initiated on it from January 2005 to August 2010. Only patients who remained on methotrexate monotherapy for at least 7 months were included, and they were prospectively followed for 3 years. The dosage of methotrexate used was allowed to vary according to disease severity. Patients had the option to change to biologic disease-modifying anti-rheumatic drugs in case of worsening disease and/or emergence of a significant adverse event.

All patients had high baseline disease activity, as supported by a mean Disease Activity Score in 28 joints (DAS28)-erythrocyte sedimentation rate (ESR) of 5.2, a mean DAS28-C-reactive protein (CRP) score of 4.5, and progressive joint destruction as measured by a mean van der Heijde-modified total Sharp Score (TSS) of 18.6.

The mean dosage of methotrexate used was 4.3 mg/wk at baseline, 6.7 mg/wk after 1 year, 7.0 mg/wk after 2 years, and to 6.8 mg/wk after 3 years. Prednisolone was prescribed to 23.6% of patients, with a mean dosage of 5.0 mg/day at baseline, 4.2 mg/day after 1 year, 3.7 mg/day after 2 years, and 3.5 mg/day after 3 years.

"Disease activity was found to be significantly improved each year starting at baseline and continuing to 3 years," the investigators stated. From baseline to 3 years, the DAS28-ESR decreased from 5.2 to 3.9 (P<0.0001) and the DAS28-CRP decreased from 4.5 to 3.1 (P<0.0001). The percentage in DAS28-ESR remission increased from 1% to 19%, and the percentage achieving DAS28-CRP remission increased from 4% to 39%.

The mean score on the modified Health Assessment Questionnaire (mHAQ) improved from a mean of 0.54 at baseline to 0.18 at 3 years (P<0.0001), and the mHAQ remission rate improved from 16% to 60 % over the same time. The ratio of patients who achieved Boolean remission also increased from 0.8% to 24.0% over the 3 years.

The ratio of patients classified as being in structural remission increased yearly, from 38.5% at year 1 to 50.4% at year 3, those classified as having a change in their TSS >3 decreased from 34.2% to 20.4% and those classified as having evidence of rapid progression declined from 21.7% to 10.9% over the same period.

In support of their finding, Shiowaza and colleagues pointed to an earlier study in Caucasian patients showing that 30% on methotrexate monotherapy did not require combination therapy.

"Our observations may more closely represent the outcomes to be expected with low-dose methotrexate monotherapy in a typical real-life patient population, and indicates that methotrexate monotherapy may be useful as a first-line drug to halt radiographic evidence of progression in RA," they wrote.

They concluded, "These results support the rationale for the use of methotrexate monotherapy as a first choice to halt radiographic evidence of progression, unless or until disease becomes active and/or adverse events appear."

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